Biological Sciences€¦ · environment and maintain biological homeostasis. The result of the metabolic adaptation can be observed as characteristic metabolic phenotypes in the metabolic

【Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)】 Biological Sciences

Title of Project： Transomic Analysis of Metabolic Adaptation

Shinya Kuroda (The University of Tokyo, Graduate School of Science, Professor)

Research Project Number：17H06299 Researcher Number：50273850

【Purpose of the Research Project】 Living organisms dynamically adapt their

metabolism in response to change in surrounding environment and maintain biological homeostasis. The result of the metabolic adaptation can be observed as characteristic metabolic phenotypes in the metabolic syndrome, diseases and pathological phenomena. For example, the blood glucose level in fasting human is maintained constant, but in diabetes, the homeostasis of blood glucose is lost and hyperglycemia appears. These metabolic adaptations are dynamic phenomena where metabolism adapts along with time from a normal base state to an adaptive state on metabolic network of over 1000 metabolites.

Metabolic adaptation is not controlled only by metabolite (metabolome) changes. Genome, epigenome, transcriptome, and proteome locates in upper layer of metabolome and they can also control metabolic adaption. These omic layers shape transomic network and closely interact each other. Therefore, metabolic adaptation can be recognized as dynamical switching of the complex transomic network (Fig. 1). Due to the complexity, understanding metabolic adaptation needs simultaneous measurements of multiple omics data and needs technology development of transomic analysis that integrates multi-layer omics data across the hierarchy.

In this research area, we aim to achieve a unified understanding of individual phenomena as metabolic adaptation through transomic analysis.

【Content of the Research Project】

We measure genome, epigenome, transcriptome, proteome and metabolome by preparing samples under the same condition for various phenomena

such as type 2 diabetes, cancer, inflammatory disease, and drug resistance. We perform transomic analysis to understand the mechanism of metabolic adaptation using both hypothesis-driven approach based on biological knowledge and data-driven approach based on statistics. We also improve throughput and sensitivities of omics measurements. Moreover, we develop advanced technologies of transomic analysis that integrate multiple layers based on various databases and statistical and information science for comprehensive understanding of the transomic network.

【Expected Research Achievements and Scientific Significance】

Conventionally, metabolic adaptation has been studied as individual life phenomena in different fields. In contrast this research area enables to understand these phenomena in a unified way as metabolic adaptation from the viewpoint of switching of transomics network. Furthermore, as a common strategy beyond individual phenomena, master switches to switch transomic network, biomarkers, and multidrug target molecules will be identified. We also clarify robust network structures which are commonly observed in many transomic networks of different molecules. In more future, as life innovation, we expect identification of environmental factors of disease as well as genetic factors through Trans-OWAS (Trans-Ome-Wide Association Study). As green innovation, novel strategies for useful compound production using microbes and for breeding plants resistant to climate change are expected.

【Key Words】 Transomics analysis: an analysis to integrate multi-layer omic data (e.g. genome, epigenome, transcriptome, proteome, and metabolome) across hierarchies.

【Term of Project】 FY2017-2021

【Budget Allocation】 1,224,700 Thousand Yen

【Homepage Address and Other Contact Information】 http://transomics.umin.jp/ [email protected]

Fig. 1. Metabolic adaptation is realized by switching transomic network.

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Grant-in-Aid for Scientific　Research on Innovative Areas(Research in a proposed research area)


Title of Project： Evolutionary theory for constrained and

directional diversities Shigeru Kuratani (RIKEN, Chief Scientist)

Research Project Number：17H06384 Researcher Number： 00178089

【Purpose of the Research Project】 Living organisms do not evolve perfectly in random directions, but we recognize unevenness and directionalities in phenotypic variations and evolutionary changes. Thus far, however, these directionality or evolutionary constraints have never been dealt with scientifically. In this project, we aim at detecting them at various hierarchical levels, to understand the relationships or correlations between phenotypic changes observed in a short time scale (like adaptive responses) and those observed in a longer scale as evolution, to look for mechanistic and causal logics linking between the two, and finally to establish a theoretical framework to deal with the patterns of evolution, involving classical natural selection and neutral theories.

【Content of the Research Project】 1. To quantify the phenotypic response towards environmental and developmental perturbations, and to speculate the mode of correlation between the responsive gene expression levels and the responding phenotypic variations based on the fluctuation-response theory already developed in the field of physics. Thus, we will describe and measure the correlation between responses of gene regulation and phenotypes, and fluctuating embryonic morphological patterns and resultant phenotypic variations. Variations in epigenetic regulation will also be the target of the analyses. 2. To speculate the existence of constraints in the process of phenotypic generation during evolution, by means of comparison of phenotypes among various species, and to analyse, behind the fluctuating phenotypes, how the responsible genes' expressions and developmental patterns can fluctuate. Using simple models, we aim at performing experimental evolutionary analyses (E. coli), to identify and quantify genetic factors (structure of gene expression networks) behind the constrained phenotypes. 3. Based on the results obtained in 1 and 2, and by integrating the simulation analyses using simple models as well, we aim at exploiting methodologies to analyse the relationship between phenotypic variations and evolutionary changes, as the bases for applying to multiple

systems at different hierarchical levels including complicated body plans and host-parasite symbiosis. Eventually, we will try to establish a new theoretical framework to deal with evolutionary directionality and constraints.


One major aspect of this project is the fact that it involves concepts of statistic physics to deal with so far untouchable questions in the evolutionary biology, namely, the causal and mechanistic nature of evolutionary directionalities and constraints. We also aim at establishing an integrative theory that can deal with evolutionary phenomena at various, multiple hierarchical levels like, from molecules and cell to the complex anatomical traits or ecological level evolution. The hint is already given from the field of physics and theoretical biology (fluctuation-response evolutionary theory; Kaneko and Furusawa, 2006). Not a while ago, even the quantum physics could never imagine that the field would ever be related by itself directly to the evolution of the entire universe, but now it does. Integration of the theory and observation has connected the two different worlds, which used to look so distantly related from each other. In the present project also, it is aimed at jumping over different hierarchical levels of phenomena, to show how a simple and integrative rule governs the entire world of organismal evolution and perplexing diversity surrounding us.

【Key Words】 Evolutionary biology, Evo-Devo, Evolutionary morphology, Experimental evolutionary biology, Ecology, Physics, Theoretical biology.

【Term of Project】 FY2017-2021 【Budget Allocation】1,230,800 Thousand Yen

【Homepage Address and Other Contact

Information】 http://constrained-evo.org/

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Title of Project： Principles of pluripotent stem cells underlying

plant vitality Masaaki Umeda (Nara Institute of Science and Technology, Graduate School of Biological Sciences, Professor)

Research Project Number：17H06470 Researcher Number：80221810 【Purpose of the Research Project】

Plants can survive extended periods if the environmental conditions favor continuous growth. This suggests the presence of a persistent source generating new organs, namely plant stem cells. In plants, stem cells produce other stem cell populations, which then generate new organs at various positions of the plant. For example, stem cell populations produced at the shoot apex are positioned at the axillary bud and generate new stems, leaves, and flowers (Fig. 1). This implies that these stem cells possess pluripotency, which enables repeated production of organs. In animals, pluripotent stem cells disappear soon after early embryogenesis, and in the adult body, tissue stem cells capable of differentiating into specific cell types are involved in the maintenance of tissue homeostasis (Fig. 1). In contrast, plant stem cells proliferate and are scattered throughout the plant body, and each stem cell population exhibits a continuing pluripotency. This feature enables continuous growth of plants, whereas the rapid disappearance of pluripotent stem cells in animals prevents post-embryonic organ formation. This project aims to answer these key questions: How do plants augment pluripotent stem cell populations in vivo, and how do plants maintain them over long periods of time?

【Content of the Research Project】 To understand the mechanisms of proliferation and maintenance of pluripotent stem cells in plants, we intend to investigate the machinery of stem cell division and the regulatory system underlying maintenance of pluripotency and genome integrity. One of the major themes is to elucidate the role of plant hormones in modulating asymmetric division that produces stem cells and differentiated cells. Another focus is on the generation of stem cells through reprogramming, which occurs easily in plants. Regarding stem cell maintenance, we plan to investigate the key factor regulating the loss of pluripotency during the floral transition stage. Comparative analyses of transient and permanent stem cells will be performed to understand the chromatin-level regulation of pluripotency. Furthermore, research on regeneration of stem cells that is required for the maintenance of genome integrity under stressful conditions will be performed. Genome plasticity that allows for accrual of DNA mutations and contribution to genomic diversity in the progeny will be explored. 【Expected Research Achievements and Scientific Significance】

Reprogramming of somatic cells and long-term maintenance of pluripotent stem cells normally occur during plant development; thus, plants are assumed to have a higher ability to exhibit pluripotency than animals. Understanding plant stem cells will shed light on the principles of pluripotency, and our project will uncover the survival strategy of plants that enables high vigor under changing environmental conditions.

【Key Words】 Pluripotent stem cells: Cells capable of differentiating into many cell types.



【Homepage Address and Other Contact Information】 http://www.plant-stem-cells.jp/

Figure 1. Pluripotent stem cells in plants and animals.

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Title of Project： Toward an integrative understanding of

functional zones in organelles

Shigeomi Shimizu (Tokyo Medical and Dental University, Medical Research Institute, Professor)

Research Project Number：17H06413 Researcher Number： 70271020 【Purpose of the Research Project】

Organelles are small, specialized structures in cells, which play specific roles to regulate various cellular events. The recent rapid development of imaging techniques have clarified the details of organelle dynamics, demonstrating that (1) various functional regions are dynamically formed within organelles, (2) organelle functions are made possible by the comprehensible actions of these functional regions. We named these local functional organelle regions as “zones”. By analyzing organelle zones, we will shift organellar research towards organellar zone research. Therefore, our aim is to identify novel functions and roles of organelles by elucidating the nature of various organelle zones and the interactions between them.

【Content of the Research Project】 We will study three organelle zones, namely, the “response zone”, “communication zone”, and “sorting zone”. The “response zone” is a specific functional region that appears in organelles in response to various stressors. The “communication zone” is a contact region that enables the exchange of various molecules between different organelles, such as the mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), which is a contact site between ER and mitochondria. The “sorting zone” is a region within the ER and Golgi apparatus, in which macromolecules are specifically modified and sorted to their appropiate destinations. The function of the Golgi apparatus has been considered to be to modify

macromolecules within a series of compartments (cis, medial, and trans) and to determine its destination at the trans-Golgi network. However, the ER and Golgi apparatus consist of several different soring zones, in which macromolecules are modified and are sorted towards their final destination. We will hence analyze the nature of these sorting zones, such as the “sugar chain-modifying sorting zone”. In this project, we will identify molecules required for these organelle zones, elucidate the molecular mechanisms of zone formation, analyze these organelle zones spaciotemporally, and investigate their biological roles. Furthermore, we will elucidate the organic linkage between each organelle zone that regulates various cellular events, and investigate diseases that occur due to defects in these organelle zones. 【Expected Research Achievements and

Scientific Significance】 By conducting our study with the novel concept of “organelle zones”, we hope to elucidate the molecular machinery of organelle responses and organelle communication in various cellular situations. We also hope to elucidate the molecules and mechanisms of the sorting machinery in the ER and Golgi apparatus. By clarifying the nature of these organelle zones, we aim to create a paradigm shift from organelle biology to organelle zone biology. Our project should hence develop a new style of cell biology.

【Key Words】 organelle, super-resolution microscope, cell biology



【Homepage Address and Other Contact Information】

http://www.organellezone.org

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Title of Project： Spectrum of the sex: a continuity of phenotypes

between female and male

Makoto Tachibana (Tokushima University, Institute of Advanced Medical Sciences, Professor)

Research Project Number：17H06423 Researcher Number：80303915

【Purpose of the Research Project】 Sex has been considered as binary terms; the distinct phenotypes of male or female. However, when we examined gene modified animals, human patients of disordered sex development, and various wild animals, we frequently found the sex phenotypes that locate between typical male and female. We thus propose a novel concept of sex; continuous distribution between typical male and female (sex spectrum). Individual sex should be represented as a particular point in this spectrum (positioning). Furthermore, this point can be shifted to either direction (e.g. sex reversal in fish). We aimed to reveal molecular mechanisms controlling the “positioning” and “shifting” in the sex spectrum.

【Content of the Research Project】

We try to analyze sexual phenotype quantitatively using several parameters, such as the expression levels of the sex chromosome genes, these epigenome structure, amounts of the secreted sex steroids, activities of the sex steroid receptors, and metabolic activities. It is conceivable that “positioning/shifting” in the sex spectrum are controlled by genetic and endocrine factors and influenced by environmental factors. We therefore set three research objectives, genetic factors of the sex spectrum (A01), endocrine factors of the sex spectrum(A02), and environmental factors of the sex spectrum (A03). The sex spectrum is composed of hierarchical three layers; cellular, organ and organism. We aimed to reveal molecular mechanisms that control “positioning” and “shifting” in the sex spectrum of each layer.


We can explain various sex phenomena by adopting the view of the sex spectrum. For example, we might explain the sex reversal in fish quantitatively as a positional shift in the spectrum. We believe that quantitative analysis of sex might result in the re-definition of sex. We propose two another significance of our research. First, it may enhance cultural and social understanding of human sex differences. Second, it may contribute to clinical medicine, such as understanding the onset mechanisms of disorders of sex differentiation and improving the gender-based medicine.

【Key Words】 A continuity of phenotypes between female and male Spectrum of the sex



【Homepage Address and Other Contact Information】 http://park.itc.u-tokyo.ac.jp/sexspectrum/

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Documents

Biological Sciences€¦ · environment and maintain biological homeostasis. The result of the metabolic adaptation can be observed as characteristic metabolic phenotypes in the metabolic